Bone cement system for bone augmentation

ABSTRACT

A bone cement is provided that includes a solid component and a liquid component. The solid component and liquid component are mixed together to form the bone cement. After completion of the solid and liquid component mixing, the bone cement has an initial viscosity effective for manual application or manual injection onto or into a targeted anatomical location, e.g., bone, and the cement has stable viscosity range that over both time and temperature is effective for uniformly filling the targeted anatomical location, for example an osteoporotic bone or a fractured vertebral body, with minimal to no leakage of the cement from the targeted anatomical location. Additionally, both the initial viscosity and the stable viscosity of the bone cement are within a range that renders the bone cement effective for injection with a manually operated syringe or multiple syringes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of PCT ApplicationPCT/US2011/027142 filed Mar. 4, 2011 which claims priority to U.S.Provisional Patent Application Ser. No. 61/310,759, filed Mar. 5, 2010,the disclosures of which are hereby incorporated by reference as if setforth in their entirety herein.

FIELD OF THE DISCLOSURE

The present disclosure generally relates to an improved bone cementcomposition and a bone cement system for use in bone augmentation. Inparticular, the present disclosure relates to a bone cement compositionhaving a viscosity range suitable for immediate manual injection. Theimproved bone cement of the invention also enhances the uniformity offilling and results in reduced leakage flow.

BACKGROUND

Bone cement is conventionally prepared directly prior to injection bymixing a bone cement powder, such as poly-methyl-methacrylate (PMMA), aliquid monomer such as methyl-methacrylate monomer (MMA), an x-raycontrast agent, such as barium sulfate, and an activator of thepolymerization reaction, such as N,N-dimethyl-p-toluidine to form afluid mixture. Other additives including but not limited to stabilizers,drugs, fillers, dyes and fibers may also be included in the bone cement.Since the components react upon mixing, immediately leading topolymerization, the components of bone cement are typically keptseparate from each other until the user is ready to form the desiredbone cement.

Cement leakage is undesired during vertebroplasty and other similarprocedures because it can expose patients to serious risks. Accordingly,the viscosity of the cement is an important factor at reducing unwantedleakage. Concomitant with the use of cements of increasing viscosity,however, is the use of high force injection systems. Such high forceinjection systems may even exceed human physical limits and precludeimportant tactile force feedback for the surgeon. High viscosity bonecements also may require longer wait times for the composition to reachsufficient viscosity, thereby reducing total work time. Another possibledrawback of high viscosity bone cement may be little interdigitationbetween cement and bone, thereby compromising the mechanical strength ofthe reinforced bone.

Other examples of bone cement compositions and/or their uses arediscussed in U.S. Pat. Nos. 7,138,442; 7,160,932; 7,014,633; 6,752,863;6,020,396; 5,902,839; 4,910,259; 5,276,070; 5,795,922; 5,650,108;6,984,063; 4,588,583; 4,902,728; 5,797,873; 6,160,033; US20070027230;EP1850797 and EP 0 701 824, US Pat. Appln. 2007/0032567.

Percutaneous vertebroplasty is one technique utilizing bone cement fortreating weakened or collapsed vertebrae and aids in reducing paininduced by diseases such as osteoporosis. In the vertebroplastyprocedure, a fractured vertebral body is augmented with a bone cement.The bone cement polymerizes and hardens upon injection into thevertebral body and stabilizes the fracture. Pain relief for the patientis usually immediate and vertebroplasty procedures are characterized bya high rate of success.

SUMMARY

The present disclosure describes a bone cement formed by a combinationof solid and liquid components. The solid component includes a contrastagent, a polymerization initiator, a calcium phosphate based bonesubstitute material, and a solid polymer, and the liquid componentincludes a liquid monomer, a polymerization accelerator, and optionallya polymerization inhibitor. According to embodiments of the disclosure,the bone cement has an initial injectable viscosity suitable for manualinjection onto or into a targeted anatomical location, where the initialinjectable viscosity is formed substantially immediately after combiningthe solid component and liquid component.

According to one embodiment of the bone cement, the solid componentincludes the contrast agent at a range of about 38 to about 42 percentby weight of the solid component, the polymerization initiator at arange of about 0.3 to about 0.5 percent by weight of the solidcomponent, the bone substitute material, such as hydroxyapatite, at arange of about 14 to about 16 percent by weight of the solid component,and the solid polymer, which can include one or more ofpoly(methylacrylate-co-methylmethacrylate), poly(meth)acrylate,polymethyl(meth)acrylate, poly(methylmethacrylate), and/orpoly(methylmethacrylate-co-styrene) polymers, blends, mixtures, orcopolymers, in the range of about 43 to about 46 percent by weight ofthe solid component.

According to another embodiment, the bone cement includes the contrastagent, zirconium dioxide, at about 40% by weight of the solid component,the bone substitute material, hydroxyapatite, at about 15 percent byweight of the solid component, and the solid polymer, a mixture ofpoly(methylacrylate-co-methylmethacrylate) and poly(methylmethacrylate),at about 45 percent by weight of the solid component. According to afurther embodiment, the poly(methylmethacrylate) is the range of about3% to about 15% by weight percent of the solid polymer.

According to one embodiment, the bone cement has a waiting phase of twominutes or less. According to another embodiment, the bone cement has awaiting phase of one minute or less. According to still anotherembodiment, the bone cement has a waiting phase of substantially zerominutes.

According to one embodiment of the present disclosure, the bone cement,after hardening (or curing), includes the bone substitute material atabout 11 percent by weight of the hardened bone cement, the contrastagent at about 29 percent by weight of the hardened bone cement, and,the solid polymer at about 60 percent by weight of the hardened bonecement.

According to a further embodiment, the solid polymer has an averagemolecular weight range of about 200 kDa to about 1000 kDa. According toa still further embodiment, the solid polymer has an average molecularweight range of about 600 kDa to about 700 kDa. According to yet afurther embodiment, the solid polymer has an average molecular weight ofsubstantially 600 kDa. According to another embodiment, the solidpolymer includes at least a portion of substantially sphericalpolymerized beads.

According to one embodiment, the bone substitute material includessintered hydroxyapatite particles having an average particle diameterrange of about 5 um to about 50 um. According to another embodiment, thebone substitute material includes sintered hydroxyapatite particleshaving an average particle diameter range of about 10 um to about 30 um.

According to one embodiment, the bone cement can include, the contrastagent, zirconium dioxide, at about 40% by weight of the solid component;the polymerization initiator at about 0.4 percent of the solidcomponent; the bone substitute material; hydroxyapatite, at about 15percent by weight of the solid component; the solid polymer, which caninclude a mixture of poly(methylacrylate-co-methylmethacrylate) andpoly(methylmethacrylate), at about 45 percent by weight of the solidcomponent. The bone cement can further include, the liquid monomer,methylmethacrylate, at about 99.3 percent by weight of the liquidcomponent; the polymerization accelerator, N—N-dimethyl-para-toluidine,at about 0.7 percent by weight of the liquid component; and optionally,the polymerization inhibitor, hydroquinone, at about 60 ppm of theliquid component.

According to some embodiments of the disclosure, the bone cement has aninitial injectable viscosity greater than 50 Pa·s. According to anotherembodiment, the bone cement has a waiting time of less than about 2minutes. According to a further embodiment, the bone cement has awaiting time of substantially about zero minutes. According to yetanother embodiment, the targeted anatomical location is one or morevertebrae. According to still another embodiment, the bone cement, afterapplication, displays minimal leakage from the targeted location.

According to the present disclosure, a bone cement kit for treatment ofa targeted anatomical location is disclosed including a first containerhousing a solid component, including a contrast agent, polymerizationinitiator, calcium phosphate based bone substitute material, and solidpolymer; and, a second container containing a liquid component includinga liquid monomer, polymerization accelerator, and optionallypolymerization inhibitor. The solid component and liquid component arecombinable to form a bone cement having an initial viscosity suitablefor manual injection onto or into a targeted anatomical location withminimal leakage. The kit can further include, optionally, one or moresyringes adapted to inject the bone cement.

According to further embodiments of the disclosure, a method isdisclosed for the preparation of the bone cement according to any of theembodiments of the disclosure. The steps can include:

filling a first container with a solid component including a contrastagent, polymerization initiator, calcium phosphate based bone substitutematerial, and solid polymer;

filling a second container with a liquid component including a liquidmonomer, polymerization accelerator, and optionally polymerizationinhibitor; and

combining the liquid component and the solid component using a mixer.

According to another embodiment of the present disclosure, a method isdisclosed for treating a targeted anatomical location with a bone cementincluding the step of manually injecting or applying the bone cementaccording to any of the embodiments of the present disclosure, onto orinto the targeted anatomical location. According to a furtherembodiment, the step of manually injecting includes manual actuation ofa first syringe that produces a hydraulic pressure to effect theinjection or application of the cement housed in a second syringe.

According to still another embodiment of the present disclosure, amethod is disclosed, for augmenting, replacing or treating, weakened orcollapsed vertebrae using bone cement. The method can include the stepof manually injecting the bone cement according to any of theembodiments of the disclosure, onto or into one or more vertebrae.According to a further embodiment, the step of manually injectingincludes manual actuation of a first syringe that produces a hydraulicpressure to effect the injection or application of the cement housed ina second syringe.

Additionally, the bone cement has a viscosity profile over a range oftime and temperatures that lengthens the time period during which manualinjection can be undertaken. The shortening and/or substantialelimination of a waiting phase due to the relatively high initialinjectable viscosity, in combination with the viscosity profile of thecement over a range of time and temperatures, allows a user of the bonecement to prolong the application time, and reduce the leakage profilefor injecting the bone cement. Additionally, the initial viscosity andthe viscosity profile of the bone cement are within a range that rendersthe bone cement effective for injection with a manually operated syringeor multiple syringes, rather than a high pressure injection system. Thisfeature is advantageous because high pressure injection systems can lacktactile force feedback.

In addition, the bone cement of the present disclosure provides thebenefits of diminished waiting times and increased application times.According to certain embodiments, the bone cement is ready forapplication or injection immediately upon combination or mixing.Therefore, for such embodiments the waiting time for the bone cement maybe shortened to two minutes or less without compromising the safety ofthe procedure. For other embodiments, the waiting time will be zerominutes as opposed to waiting times for prior art vertebroplasty cementsthat typically range from 2 to 7 minutes (at around 22° C.). Accordingto some embodiments, the bone cement of the present disclosure can havean application time of at least 15 minutes or more for a temperaturerange from 19-27° C. as opposed to prior art vertebroplasty cements thattypically range from 5 to 12 minutes (at around 22° C.).

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings illustrate generally, by way of example, but not by way oflimitation, various embodiments discussed in the present document. Theforegoing summary, as well as the following detailed description ofpreferred embodiments of the application, will be better understood whenread in conjunction with the appended drawings.

FIG. 1 is a graphical representation of a molecular weight distributionfor solid polymer powder component embodiments and for cured bone cementembodiments according to the present disclosure;

FIG. 2 is a graphical representation of viscosity measurements over timeat different ambient temperatures of a bone cement according to someembodiments;

FIG. 3 is a graphical representation of initial viscosity measurementsat different ambient temperatures of the bone cement according to someembodiments;

FIG. 4 is a graphical representation of application time, hardening timeand initial viscosity at different ambient temperatures of the bonecement, according to some embodiments;

FIG. 5 is a graphical representation of injection force curves forinjecting the bone cement at different ambient temperatures according tosome embodiments;

FIG. 6 is a graphical representation of injection force curves forinjecting the bone cement using various gauged needles according to someembodiments;

FIG. 7 is a graphical representation of application times for applyingthe bone cement using various gauged needles, according to someembodiments;

FIG. 8A is a graphical representation of viscosity measurements of twobone cements as a function of time after mixing (Cement I: bone cementformulation according to prior art; Cement II: bone cement formulationaccording to an embodiment of the present disclosure;

FIG. 8B is a graphical representation of initial viscosity measurementsof the bone cements, Cement I and Cement II of FIG. 9A;

FIG. 9A is a perspective view of a micro-computed tomography image ofosteoporotic cancellous bone;

FIG. 9B is a perspective view of a micro-computed tomography of acancellous bone substitute;

FIG. 10 is a schematic view of a porous bone substitute sample preparedaccording the Baroud Model discussed herein;

FIG. 11 is a graphical representation of leaked mass and leakage time ofCement I and Cement II according to the Baroud Model discussed herein;

FIG. 12 is a graphical representation of the average filling pattern ofCement I and Cement II, according to the Baroud Model discussed herein;

FIGS. 13A-E, are cross-sectional views of porous substitute samplestested under the Baroud Model for Cement I over a range of initialinjection viscosities;

FIG. 13F is a cross-sectional view of a porous substitute sample testedunder the Baroud Model for Cement II at initial injection viscosity;

FIGS. 14A, B, C, D, E, illustrate degrees of Cement I bone cementextrusion from a syringe over a range of initial injection viscosities;

FIG. 14F illustrates Cement II bone cement extrusion from a syringe atinitial injection viscosity.

DETAILED DESCRIPTION

In order that the present disclosure may be more fully understood thefollowing definitions are set forth:

The term(s) “waiting phase” or “waiting time” as used herein refer tothe time interval after the completion of mixing of the solid and liquidcomponent to form the bone cement, and the bone cement reaching aninjectable viscosity level.

The term “injectable viscosity” as used herein refers to a minimumviscosity level suitable for manual application and/or manual injectionof the bone cement according to the present disclosure.

The term, “initial viscosity,” as used herein, refers to the viscositymeasured during the rheological data acquisition in a test known as theViscosity Measuring Test. Rheological data acquisition was performed asfollows: Initial viscosity was derived from rheological investigation ofthe cement viscosity as a function of time after start of the bonecement preparation. For the viscosity measurements, 3 mL of preparedbone cement were placed in a rotational rheometer (RheolabQC,Anton-Paar, Graz, Austria) with a custom designed double gap measurementsystem made of PMMA-resistant polypropylene. Real viscosity (η′) andambient temperature (T) were recorded directly to a personal computer.The rheometer was set to operate at an oscillatory frequency of 1 Hz anda maximum torque of 3 mN·m. Data was recorded at a frequency of 0.2 Hz.Viscosity measurements were started 2 min. after start of mixing of thesolid and liquid components. Rheometer measurements were stopped at aviscosity of 3000 Pa·s. In order to investigate the cement viscosity sixtrials were performed at each ambient temperature (19, 21, 23, 25 and27° C., respectively). Temperature was controlled using anair-conditioned lab. Humidity of the lab was controlled and was higherthan 40%. Accuracy at ambient temperature was ±0.5 K. Cement viscosityas function of the time after start mixing was presented with onerepresentative measurement for each ambient temperature includingstandard deviation bars at given cement viscosity levels (50, 200, 500,1000 and 1500 Pa·s). Initial viscosities for the various ambienttemperatures were presented as means and standard deviations (mean±SD).

The term “application time” as used herein, refers to the time intervalafter the start of mixing of the solid and liquid bone cement componentsand the bone cement reaching an injection force of 90 N.

The term, “leaked mass of cement,” as used herein, refers to the amountof cement that leaks through a leakage model described in 2006 by Baroudet al., “High-Viscosity Cement Significantly Enhances Uniformity ofCement Filling in Vertebroplasty: An Experimental Model and Study onCement Leakage,” SPINE, 31 (22), 2562-2568 (2006), hereinafter, “BaroudModel” the disclosure of which is hereby incorporated by reference inits entirety Features of the Baroud Model are also discussed in thefollowing article: Baroud et al., “Experimental and theoreticalinvestigation of directional permeability of human vertebral cancellousbone for cement infiltration,” J. Biomech., 37, 189-196, (2004), thedisclosure of which is hereby incorporated by reference in its entirety,and are explained further herein.

The term “leakage time” as used herein refers to the amount of timeelapsed after start of mixing the solid and liquid bone cementcomponents and the observation of cement leakage that leaks undertesting performed according to the Baroud Model as explained further inExample 1.

The term, “injection force,” as used herein refers to the Newton's offorce required to inject cement into bone under testing known as theInjection Force Measuring Test (the “injection test”). Syringes andinjection needles used in the injection test setup were similar to thoseused in vertebroplasty surgery. One ml syringes (Synthes GmbH) wereattached to side opening needles of 8 Ga, 10 Ga and 12 Ga. (SynthesGmbH). The needles presented an inner diameter of 3.2, 2.6 and 1.9 mm,and a length of 176.1, 155.7 and 155.35 mm for the named 8 Ga, 10 Ga and12 Ga needles, respectively. Those were mounted on an Instron 5866universal testing machine (Instron, Canton, USA) equipped with a 1.0 kNloadcell to measure injection forces. Injection was performed using avolume flow rate of 0.75 mL/min. Data was recorded at a frequency of 0.2Hz.

The term, “hardening time,” as used herein refers to the time elapsedbetween mixing the solid and liquid components and hardening or curingof the bone cement.

A bone cement according to the present disclosure is formed from thecombining of a solid component (typically constituted in a powder orparticle form) and a liquid component that, when combined (e.g., viamixing), form a bone cement having both a relatively high initialviscosity and substantially long application time that is effective foruse in manually operated syringe injection systems. The bone cement hasan initial injectable viscosity and can be manually injectedsubstantially immediately after completion of mixing, which can limitthe waiting phase according to some embodiments to substantially lessthan two minutes, and according to other embodiments, the waiting phasecan be shortened to substantially about zero minutes. Additionally, thebone cement has a viscosity profile over a range of time andtemperatures that lengthens the time period during which manualinjection can be undertaken. The shortening and/or substantialelimination of a waiting phase due to the relatively high initialinjectable viscosity, in combination with the viscosity profile of thecement over a range of time and temperatures, allows a user of the bonecement to lengthen the application time, and reduce the leakage profilefor injecting the bone cement for a desired procedure. Such procedurescan include for example vertebroplasty, kyphoplasty, and cementaugmentation applications

The solid component of the bone cement, includes a contrast agent, abone substitute material and a solid polymer. Suitable contrast agentspermit the bone cement to have a radiopacity effective for viewing thebone cement both while it is being injected and once it is injected at abone site. The radiopacity feature of the bone cement permits thedisplay of any minimal leakage of the cement mixture, once the bonecement mixture is injected into bone using fluoroscopic instruments.Suitable contrast agents can include for example, zirconium dioxide,barium sulfate and/or titanium dioxide and mixtures and blends thereof.The contrast agent can be present according to one embodiment in a rangeof about 30% to about 60% by weight of the solid component; in anotherembodiment about 35% to about 45% by weight of the solid component; andin still another embodiment about 38% to about 42% by weight of thesolid component.

Suitable bone substitute material can include any ceramic compositescapable of mimicking the physiological and morphological features ofbone, and can include calcium phosphate based compounds, for example,hydroxyapatite Ca₁₀(PO₄)₆(OH)₂. According to one embodiment, the bonesubstitute material is in sintered particle form, for example, sinteredhydroxyapatite particles, and can have an average particle diameterrange of about 5 um to about 50 um, and preferably from about 10 um toabout 30 um. The bone substitute material can be present according toone embodiment in a range of about 0% to about 20% by weight of thesolid component; in another embodiment about 12% to about 18% by weightof the solid component; and in still another embodiment about 14% toabout 16% by weight of the solid component.

Suitable solid polymer can include (meth)acrylic polymers, for example,polymethyl(meth)acrylate, poly(methylmethacrylate),poly(methylacrylate-co-methylmethacrylate) and/orpoly(methylmethacrylate-co-styrene). The solid polymer can includehomopolymers and copolymers of the (meth)acrylic polymers as well asmixtures and blends thereof. The solid polymer can be present accordingto one embodiment in a range of about 35% to about 55% by weight of thesolid component; and in another embodiment about 43% to about 46% byweight of the solid components. In a preferred embodiment, the solidpolymer includes a mixture of the copolymerpoly(methylacrylate-co-methylmethacrylate) and the homopolymerpoly(methylmethacrylate). In a particularly preferred embodiment, thehomopolymer poly(methylmethacrylate) is in a range of about 3% to about15% by weight of the solid polymer.

The physical and chemical characteristics of the solid polymer portion(typically in a powdered or small particle state) of the solid componentcan contribute to the relatively high initial injectable viscosity ofthe bone cement as well as the extended application time according tothe present disclosure. These characteristics influence the wetting andswelling behaviors of the bone cement when the solid component iscombined with the liquid component to form the bone cement. Suchcharacteristics of the polymer powder particles can include, forexample: shape and morphology; surface area and texture; and, averagemolecular weight range and particle size and distribution. One suchexample, the variation of the solid polymer particle size distributionto alter the viscosity properties of a cement, is described in Hernandezet al., “Influence of Powder Particle Size Distribution on ComplexViscosity and Other Properties of Acrylic Bone Cement for Vertebroplastyand Kyphoplasty,” J. Biomed. Mater. Res.; Part B: Appl. Biomater., 77B(1), 98-103 (2006) (first published online Oct. 20, 2005 atwww.interscience.wiley.com), the disclosure of which is herebyincorporated by reference in its entirety. According to one embodimentof the present disclosure, the solid polymer includes polymerizedparticles having a relatively high surface to volume ratio, preferablysubstantially spherical beads. Referring to FIG. 1, a molecular weightdistribution graph is depicted for the solid polymer of the bone cement(Curve 1) and for the bone cement in its cured or hardened state (Curve2). According to one embodiment, the solid polymer can have an averagemolecular weight range of about 200 kDa to 1000 kDa. In a preferredembodiment the average molecular weight range of the solid polymer isabout 600 kDa to about 700 kDa, and in a more preferred embodiment, theaverage molecular weight is substantially about 600 kDa.

The solid component further includes a polymerization initiator, forexample, dibenzoylperoxide. The initiator can be present according toone embodiment in a range of about 0.2% to about 0.6% by weight of thesolid component; in another embodiment about 0.3% to about 0.5% byweight of the solid component; and in still another embodiment about0.35% to about 0.45% by weight of the solid component.

According to one embodiment, the bone cement composition includes about11+/−0.1% by weight of bone substitute material, about 29.3+/−0.1% byweight of a contrast agent and about 59.7+/−0.1% by weight of a solidpolymer based upon a weight percentage of the hardened or cured bonecement. According to another embodiment, the solid component of the bonecement includes hydroxyapatite, zirconium dioxide, and a solid polymer.

The liquid component of the bone cement, according to one embodiment caninclude a polymerization accelerator and a monomer capable ofpolymerization. The liquid component can further include, according toanother embodiment, a polymerization inhibitor that reduces or impedesautopolymerization of the monomer. According to one embodiment, asuitable polymerization accelerator includes N—N-dimethyl-p-toluidin(DMPT). DMPT can be present, according to one embodiment in a range ofabout 0.4 to about 1.0% by weight of the liquid component; in anotherembodiment about 0.5% to about 0.9% by weight of the liquid component;and in still another embodiment about 0.6% to about 0.8% by weight ofthe liquid component. According to one embodiment, a suitable monomerincludes methyl methacrylate (MMA). MMA can be present, according to oneembodiment in a range of about 99.0% to about 99.8% by weight of theliquid component; in another embodiment about 99.1% to about 99.7% byweight of the liquid component; and in still another embodiment about99.3% by weight of the liquid component. A suitable polymerizationinhibitor includes hydroquinone, according to one embodiment and can bepresent in a range of about 60 ppm of the liquid component.

According to one embodiment, the bone cement includes a solid componenthaving a solid polymer in a weight percentage of 44.6+/−0.1% of thesolid component; a contrast agent in a weight percentage of 40.0+/−0.1%of the solid component; a bone substitute material in a weightpercentage 15.0+/−0.1% of the solid component; and a polymerizationinitiator in a weight percentage of 0.4% of the solid component.According to another embodiment, the bone cement includes a solidcomponent having a copolymer poly(methylacrylate-co-methylmethacrylate)and homopolymer poly(methylmethacrylate) blend as a solid polymer,zirconium dioxide as a contrast agent, hydroxyapatite as a bonesubstitute material and dibenzoylperoxide as a polymerization initiator.

According to one embodiment, the bone cement has a liquid componenthaving a monomer in a weight percentage of 99.35+/−0.1% of the liquidcomponent; a polymerization accelerator in a weight percentage of0.65+/−0.1% of the liquid component. According to another embodiment theliquid component is stabilized with about 60 ppm of a polymerizationinhibitor. According to a further embodiment, the bone cement has aliquid component having MMA as the monomer, DMPT as the polymerizationaccelerator, and hydroquinone as the polymerization inhibitor.

According to one embodiment, the bone cement is part of a bone cementapplication system that also includes a mixer for mixing the powder andliquid. The liquid and solid components of the bone cement are typicallyseparated until intended to be mixed by a technician, doctor or othersuitable user. According to one embodiment, the bone cement applicationsystem includes a container that contains a pre-filled solid component,the container being sealed with a sterilization cap, and a glass ampoulefilled with the liquid component, the ampoule having a crushing ring.The system can further include a transfer cap for transferring the bonecement, after the mixing of the solid and liquid components, to theapplication system.

Bone cement embodiments described herein are formed by the solidcomponent and liquid component. The solid component and liquid componentcan be packaged separately, for some embodiments, or together for otherembodiments to form a system for manual syringe injection. According toone embodiment manual syringe injection can be accomplished through asystem of more than one syringe where manual actuation of one syringeproduces a hydraulic pressure to effect the injection of the cementhoused in another syringe. According to another embodiment, the manualinjection is accomplished directly through manual actuation of a singlesyringe housing the cement. Once the powder and liquid component aremixed, the bone cement forms. The final cured or hardened bone cementcomposition includes, for some embodiments, about 11% bone replacementmaterial, about 29.3% of the contrast agent and about 59.7% of thepolymer by weight. It should be appreciated that the polymer weightpercentage of the cured bone cement includes both the polymer weightpercentage of the solid polymer of the solid component as well as theweight percentage of the polymerized liquid monomer of the liquidcomponent.

The development of viscosity or a viscosity range, such as initialviscosity, in bone cement is an important factor in working time of thebone cement, the injection force necessary to deliver the bone cement tothe targeted anatomical location, the time required for the bone cementto effectively harden or set, and the amount and/or rate of leakage ofthe bone cement from the targeted location. Viscosity curves for a bonecement according to one embodiment are shown in FIGS. 2 and 3 recordedafter the start of mixing of the solid and liquid components attemperatures of 19° C., 21° C., 23° C., 25° C., and 27° C.,respectively. The graph shows that the rate of increase in viscosity(measured in Pa·s) is greater at the higher temperatures than at thelower temperatures. At 800 seconds after the start of mixing, theviscosity of the bone cement at 19° C. was about 380 Pa·s. This comparesto a viscosity of over 1600 Pa·s at 800 seconds after the start ofmixing at temperature of 27° C.

FIG. 3 is a zoom view of FIG. 2 and focuses on the initial viscosity ofthe bone cement at temperatures of 19° C., 21° C., 23° C., 25° C., and27° C., respectively, over a time period of 100 to 300 seconds after thestart of mixing the solid and liquid components. The rate of increase ininitial viscosity is flatter over time across all temperatures than theoverall viscosity changes shown in FIG. 2. At 200 seconds from the startof mixing, the initial viscosity of the bone cement was about 70 Pa·s at19° C., while at 27° C. the initial viscosity was about 170 Pa·s.

FIGS. 2 and 3 illustrate that the initial viscosity of the bone cementmaintains stability over a range of temperatures. All initialviscosities shown in FIG. 3 are suitable for injection; i.e., allviscosities shown are initial injectable viscosities. The bone cementhas an initial viscosity range between 70-140 Pa·s at all measuredtemperatures within two minute after mixing has started.

The bone cement system described herein shortens the waiting phase tosubstantially zero minutes, according to one embodiment, withoutcompromising the safety of the procedure to be performed, for example avertebroplasty procedure. Additionally, the bone cement can transitionto a second stable viscosity that over a range of suitable time andtemperature can enable a uniform filling of the targeted anatomicallocation with minimal or no leakage of the bone cement to adjacenttissue due to the hardening behavior of the bone cement in situ.

Hardening behavior of the bone cement was characterized usingrheological measurements, polymerization temperature investigations,injection force measurements, and a hands-on knocking test where thebone cement was tested manually on walnut sized, spherical formed bonecement samples by knocking them on the table. Because the temperatureinfluences the hardening behavior enormously (hardening rates increasewith increasing temperature), hardening behavior was investigated atdifferent ambient temperatures, as well as at 37° C. to simulate bodytemperature. According to one embodiment, the hardened or cured bonecement can have a glass transition temperature range of about 100° C. toabout 125° C.

The injection test was performed as follows: After cement preparation,the cement was filled in ten 1 ml syringes. A first syringe was mountedon the injection needle. Injection was started with a delay of 5 min and10 min after the start of mixing for the tests performed at ambienttemperature of 23, 25, 27° C. and 19, 21° C., respectively. Injectionwas performed using volume flow rate of 0.75 mL/min (stepwise injection)followed by the injection of the other syringes until an injection forceof 150 N was recorded due to the polymerization and hardening of thecement sample. The flow rate was chosen at the lowest limit of averageclinical measurements, and the hardening time was determined as the timeelapsed after the start of mixing and the cement reaching a hardenedstate.

FIG. 4 illustrates that hardening time decreases with increasingtemperature, from about 33 minutes from the initiating of mixing at 19°C., to about 19 minutes from the initiating of mixing at 27° C.Application time also decreases with temperature, from about 31 minutesfrom the initiating of mixing at 19° C., to about 17 minutes from thestart of mixing at 27° C. These times and temperatures fall withinacceptable ranges for performing the vertebroplasty procedure.

Injection force required to move the bone cement into bone increaseswith increasing temperature, as shown in FIG. 5. For example, at 15minutes after start mixing the injection force at 19° C. is about 21 N,while the injection force at 27° C. is about 60 N. The rate of increaseof injection force is greater for cement mixtures at 27° C., than at 19°C. These injection forces are within a range wherein hand-operatedsyringes are usable.

In addition to temperature, adjustment in the size of needle gauge usedto inject the bone cement in bone has an impact injection force overtime, as shown in FIG. 6. The data displayed in FIG. 6 was obtained atroom temperature. The data shows that the injection force increases overtime as the gauge of the syringe increases from 8 to 10 to 12 gauge(i.e., as syringe diameter decreases). Specifically, FIG. 6 shows thatthe injection force was about 30 N for the 8 gauge and about 80 N forthe 12 gauge at 800 seconds after the start of mixing the solidcomponent and liquid component. The rate of increase of injection forceover time is faster for the higher gauge needle than for the lower gaugeneedle. The test results obtained for the injection force ranges are allwithin a range that permits a use of manually operated syringes toinject the bone cement to a targeted anatomical location, e.g., avertebral body.

FIG. 7 shows that application time decreases with an increase in gaugenumber. Specifically, the application time for an 8 gauge needle isabout 1200 seconds and the application time for a 12 gauge needle isabout 820 seconds.

The bone cement described herein reduces the waiting phase or waitingtime for injection; that is, the bone cement as described herein reachesan initial injectable viscosity at or near the completion of mixing ofthe solid and liquid components. Additionally the bone cement providessufficient application time to complete the desired procedure, e.g., avertebroplasty. Furthermore, the bone cement has a range of injectionforces over time, temperature and syringe gauge size that enables it tobe usable in syringe systems. These properties allow a surgeon to begininjection immediately after cement preparation and to continue theprocedure without waiting for the cement to reach a minimum initialviscosity level or rushing a procedure due to a shortened applicationtime because of a concern that the bone cement will reach a viscositylevel that is too high to remain workable.

Viscosity measurements for an embodiment of the bone cement as describedherein (designated “Cement II), are shown in FIGS. 8A and 8B incomparison to a prior art bone cement formulation (designated “CementI). As can be seen in FIG. 8B, Cement II has an initial injectableviscosity, while Cement I does not. Cement I also displayed leakage inthe Baroud Model (discussed further below) when the cement was injectedat an initial viscosity of 10 Pa·s, which was the initial viscosity ofCement I immediately following the completion of mixing the componentsof Cement I. Reduction in the degree of leakage of Cement I can only beaccomplished through a delay in the injection, i.e., with a waitingphase after the completion of mixing the prior art bone cement. Thiswaiting phase allows Cement I to increase viscosity to a higher levelthat is suitable for injection. Cement II displayed minimal leakage wheninjected immediately after mixing the solid and liquid components; i.e.,Cement II was not limited with a waiting phase after completion of themixing of the solid and liquid components.

A higher uniformity of cement filling and reduced cement leakage wasobtained for Cement II compared to a range of tested viscosities ofCement I as explained in detail below in Example 1. Cement II shortensthe waiting time or waiting phase to reaching an initial injectableviscosity to at least less than one minute according to some embodimentsof the present disclosure, and in other embodiments, Cement II can havean initial injectable viscosity substantially immediately after mixingis completed. Additionally, the viscosity range of Cement II has asecond stable viscosity to allow a sufficient application time tocomplete the desired procedure with a minimal leakage profile.

EXAMPLES

Examples are provided below to illustrate embodiments of the presentinvention. These examples are not meant to constrain the presentinvention to any particular application or theory of operation.

Example 1

A study of cement leakage and cement filling performance was performedusing one embodiment of the present disclosure described herein, CementII, and a prior art cement, Cement I. Cement I is a prior artvertebroplasty cement having a low initial viscosity after preparation.In particular, Cement I is a prior art, vertebroplasty cement,identified as Vertecem Mixing Kit, Ref. 07.702.010, LOT 043R/0834,Synthes GmbH, Oberdorf, Switzerland. Cement II included a solidcomponent and a liquid component. The solid component included a solidpolymer in a concentration of 44.6% by weight of the solid component,having at least the copolymerpoly(methylacrylate-co-methylmethacrylate); a contrast agent, zirconiumdioxide in a concentration of 40.0% by weight of the solid component; abone substitute material, hydroxyapatite in a concentration of 15.0% byweight of the solid component; and a polymerization initiator,dibenzoylperoxide (100%) in a concentration of 0.4% by weight of thesolid component. The total weight of the solid component was 26.0 grams.The liquid component includes a monomer, methylmethacrylate, stabilizedwith 60 ppm of polymerization inhibitor, hydroquinone in a mass of99.35%. The liquid component also includes a polymerization acceleratordimethyl-para-toluidine of 0.65% by mass for a total volume of 10.00 ml.The liquid and solid components were contained separately and were mixedon-site.

The study was performed using the Baroud Model described in 2006 byBaroud et al., “High-Viscosity Cement Significantly Enhances Uniformityof Cement Filling in Vertebroplasty: An Experimental Model and Study onCement Leakage,” SPINE, vol. 31, No. 22, pp. 2562-2568 (2006), andBaroud et al., “Experimental and theoretical investigation ofdirectional permeability of human vertebral cancellous bone for cementinfiltration,” J. Biomechanics, 37 (2004), pp. 189-196. The Baroud Modelmeasures leakage phenomenon in vertebral body augmentation byartificially creating a path that simulates a vertebral blood vessel tofacilitate and favor the forces underlying intravertebral cement flowand to provoke cement leakage. The Baroud Model was utilized to estimateboth the leakage and filling behavior of the two vertebroplasty cements,Cement I and Cement II, and reduce the risk of leakage by identifyingthe conditions for uniform cement filling.

To perform the Baroud Model testing, cylindrical porous aluminum foams(ERC Aluminum and Aerospace, CA) were custom made to exhibit geometric,morphologic, and flow properties similar to those of vertebral bone.This aluminum foam was selected because of a well-connected, controlledporosity.

To ensure that the aluminum foam samples (hereinafter “porous substitutesamples”) had similar morphologic and flow features to those ofcadaveric cancellous bone tissue, the following steps were undertaken.The porosity of three porous substitute samples was measured, usingnon-invasive microcomputer tomography (MicroCT), and Archimedessubmersion experiments. The porosity was found to be 91.1%+/−0.6%.Porosity is a measurement of the void volume of a sample, therefore,approximately 9% of the sample is composed of aluminum, the other 91%was void. This value is relatively consistent with the porosity valuesof osteoporotic cancellous bone that had been excised from the vertebralbodies in previous studies. In healthy bone, the porosity can be as lowas 75% and in osteoporotic bone as high as 95%. The remainder of thebone is typically filled with bone marrow, fat, and blood. FIGS. 9A and9B are representative Micro CT images of the morphologic features ofboth a bone sample and a porous substitute sample, respectively,highlighting the porosity and well-connected cavities.

In addition to the porosity measurements, the permeability of poroussubstitute samples was measured using Darcy's flow protocol and wascompared to the permeability of cancellous bone. In these flowprotocols, constant flow was established through the porous substitutesamples, and the pressure drop in the through flow was measured.

The diameter and height of the porous substitute samples were 38.1 and25.4 mm, respectively. These dimensions were chosen to represent athoracolumbar vertebra, where most vertebral fractures occur. Therefore,the Baroud Model is representative in terms of geometry, as well asporosity and permeability.

A 3 mm cylindrical channel (mimicking an intravertebral blood vessel)was drilled in the main plane of the porous substitute samples to form aleakage path. To permit insertion of the bone cement injection cannula,a cylindrical channel with a diameter of 4.1 mm was drilledperpendicular to the leakage path, as shown in FIG. 10. The diameter ofthis injection channel matches the outer diameter of an 8-gauge cannula,which is representative of the gauge used to perform a vertebroplastyprocedure.

After creating the leakage path and the injection channel, each poroussubstitute sample was placed in a bath filled with a water/gelatinsolution (Kraft Canada, Inc., Don Mills, Ontario) at room temperature,according to the manufacturer's instructions (5% gelatin by mass). Thebath was then placed overnight in a refrigerator at 4° C. to allow thesolution to gel, after which the gelatin remained in the poroussubstitute sample, simulating the presence of bone marrow.

The point in time at which bone cement leakage was observed from theleakage path was recorded using a stopwatch that was started at thestart time of mixing the solid and liquid components. The injectionpressure was measured with the load cell of the materials testingsystem.

The cement that leaked through both openings of the leakage path, i.e.,the leaked mass, was collected in aluminum weighing cups (FisherScientific International, Inc. Hampton, N.H.). Boiling water dissolvedthe gelatinous material, and, thereafter, a 2.5 micron filter (Whatman,Middlesex, UK) was used separate the cement from the solution. Afterdrying the filter paper in a fume hood, the mean mass of cement that hadleaked was determined by taking the average of the cement collected fromboth openings of the leakage path.

An important addition to the experimental protocol of Baroud Model wasthat the porous substitute samples were placed in a water bath at 37±1°C., simulating human body temperature. Because the nature of thepolymerization reaction that forms the bone cement is a radicalreaction, it is accelerated at higher temperatures. In the human body,at a temperature of 37° C., the bone cement cured faster than in ambienttemperature.

Materials used in the Baroud Model were similar to those used invertebroplasty surgery and include bone cement, syringes, needles andviscometer for viscosity control.

Six experimental groups were evaluated. Five groups used Cement I,having a range of initial viscosities at injection. The sixth groupincluded Cement II, starting injection immediately subsequent to cementpreparation.

In order to perform the experiment using a 37° C. water bath, aform-stable bone marrow simulant at 37° C. was prepared. The followingsteps were followed to prepare a starch mixture which is stable at 37°C. as a bone marrow substitute: Cornstarch powder (MAIZENA®, Knorr AG,Thayngen, Switzerland) and cold water were mixed by a ratio of 1:3 bystirring thoroughly at room temperature until a uniform and homogeneousmilk-like appearance was achieved.

Next, the porous substitute samples were soaked into the starch mixtureand the mixture was heated using medium heat while stirring constantlyin the same direction. The mixture was stirred and heated until itthickened and boiled. Then stirring was stopped and the mixture was lefton heat for 1-2 minutes before heating was stopped and the poroussubstitute samples were removed. After the mixture cooled, the poroussubstitute samples were placed in a refrigerator for 1 hour. Each samplewas weighed before and after being filled with the starch mixture,assuring that at least 95% of the voids of the porous substitute sampleswere filled. The final preparation step of the Baroud model includedattaching a thin layer of around 3 mm in thickness of acrylic cement(DP-Pour, DenPlus Inc., Montreal, QC) to give the model a hard shell.This thin layer was intended to act as a simulation of the corticalshell of the vertebral body.

In order to investigate the leakage behavior for Cement I and Cement II,an 8 gauge syringe with a length of 150 mm was inserted into theinjection channel of the porous substitute sample according to theBaroud Model. The porous substitute samples, filled with the starchsolution, were place into a 37° C. water bath (simulating human bodytemperature) to reach thermal equilibrium approximately 30 minutes priorto bone cement injection.

Cement I and Cement II were each prepared according to themanufacturer's instructions using a closed mixing device. The time afterstarting mixing was recorded using a stopwatch, started at the samemoment as adding the liquid component to the solid component. A total of9 ml of the prepared cement was transferred using a luer-luer couplingadapter into three 3 ml syringes (Viscosafe Injection Kit, Ref.07.702.210, Synthes GmbH, Oberdorf, Switzerland) for injection andviscosity measurement. The first two syringes for each bone cementsample were used for injection into the porous substitute sample, and athird syringe was submitted for viscosity measurement using a viscometer(Viscosafe Viscometer, Anton Paar, Graz, Austria, SN 80215110 REF03.702.010) which was kept at 22±1° C. The viscometer records realviscosity every 5 s directly to a PC using the corresponding software(RHEOPLUS/32 Multi 128 V2.66, Anton Paar, Graz, Austria).

To perform the injection tests, a 3 ml syringe filled with cement wasattached to the 8 gauge needles and mounted on a universal testingmachine (MTS Mini Bionics 858, MTS, 14000 Technology Drive Eden Prairie,Minn., USA 55344). The starting points of cement injection into theporous substitute samples was determined by reaching a predefinedviscosity threshold as measured in real-time by the viscometer.Predefined viscosities for start injection for Cement I were 10, 50,100, 200 and 400 Pa·s, respectively. A total of 6 ml of each of theCement I samples was injected using a two-step injection of two 3 mlsyringes. The injection rate was 3.5 ml/min.

Cement II was injected directly after transferring the cement to thesyringes and mounting on the testing machine. Injection was started 3min after the start of mixing, using a cross head speed of 3.5 ml/mm.For all cement groups, the time elapsed for changing from the first tothe second syringe was 90 s.

During cement injection each of the porous substitute samples wasobserved for cement leakage from both sides of the leakage channel andthe leakage time was recorded. After the entire cement injectionprocedure ended, the leaked cement from each sample was collected andweighed, defining the leaked mass. Afterwards, each porous substitutesample (now filled with bone cement) was removed from the water bath andleft at room temperature for 2 days to assure that the cement wastotally cured. For the five groups using Cement I, five repeats weredone. Seven repeats were performed using Cement II.

To evaluate the filling pattern of the bone cement in each of the poroussubstitute samples, each sample was cut normal to the axis along theinjection pathway, into two halves, using a water-cooled diamond saw.Then each half was washed with hot water to dissolve the starchsolution. For both halves of the same sample, images were taken,digitized and analyzed for eccentricity and averaged for the samesamples as described in Baroud Model. Briefly, eccentricity is definedas the eccentricity of an ellipse having the same second moment of areaas the filled configuration. The more uniform and circular the filledpattern is, the less the eccentricity value will be. For example, in astraight line the eccentricity is one, and for a circle it is zero.

The measured endpoints were the eccentricity and the mass of leakedcement collected from the water bath at the end of each experiment. Theinfluence of the material composition of Cement II and of the initialviscosity values of Cement I (fixed independent factors) on the leakedmass and eccentricity (dependent parameters) were statisticallyanalyzed. Overall statistical analysis on the resulting six materialgroups was performed using univariate ANOVA. Because of the significantdifferences received from ANOVA (p<0.006), multiple post hoc comparisonswere done by performing Tukey HSD test. In all cases, a p-value of ≦0.05was used as significance limit. Statistical analyses were performedusing SPSS software version 15.0. The observed leakage profiles of thetested porous substitute samples are illustrated in FIGS. 13A-F. FIGS.13A-E illustrate the Cement I cross-sections at a start injectionviscosity of 10 Pa·s, 50 Pa·s and 100 Pa·s, 200 Pa·s and 400 Pa·s,respectively. FIG. 13 F illustrates the Cement II cross-section injectedsubstantially immediately after mixing.

FIG. 11 graphically illustrates leaked mass as a function of startingviscosity. Qualitatively, high leakage mass was observed for Cement Iwhen injected at low viscosity levels (e.g. 10 Pa·s). The values shownin FIG. 10 correspond to the filling patterns observed for thecorresponding Cement I samples in FIGS. 13A-E. A more uniform fillingcould be obtained using higher injection viscosities up to 400 Pa·s forCement I.

As received from ANOVA testing, the leaked mass in the Cement I groupsdecreased with the increase of the starting viscosity from 10 to 400Pa·s. 2.56±0.98 g of Cement I leaked when the cement was injected at aninitial viscosity of 10 Pa·s. Delaying the injection of Cement I, i.e.,increasing the waiting phase after mixing, resulted in an increasedstarting viscosity and a corresponding reduction of the leaked cementmass. When injected at an initial viscosity of 400 Pa·s, only 1.07±0.82g of Cement I leaked.

For Cement II, no waiting phase was required and only minimal leakagewas observed. More specifically, the average leaked amount was 0.36±0.54g and the absolute leaked mass was below 1 g for all tests performed.Furthermore, of the seven leakage models injected with Cement II, therehave been three observations without leakage.

Due to the high scattering of the data, especially the data receivedfrom the Cement I groups, statistical difference was low in general.Significant differences in leaked mass could be obtained between CementI group injected at 10 Pa·s and the Cement II group injected directlyafter mixing (p=0.003), shown in FIG. 10. With a p-value of 0.084(0.173) the difference between the Cement I groups 10 Pa·s through to400 Pa·s, the leaked mass showed a clear trend in reduced leakage forhigher injection viscosity. Comparing the Cement I group injected at 50Pa·s and Cement II showed also a clear trend in reduced leakage rateusing Cement II with a p-value of 0.061. All other pairs yield nosignificant results presenting p-values higher than 0.275.

Uniformity of the filling patterns quantified by the eccentricity forthe Cement I groups have shown no statistically significant differencesin uniformity with the increase in injection viscosity, as measuredgraphically in FIG. 12 and shown in FIGS. 13 A-E. Cement II had arelative low eccentricity as measured in FIG. 12 and illustrated in FIG.13F. Statistical evaluation of the eccentricity values received from theCement II testing samples showed significantly lower eccentricity incomparison to the Cement I groups injected at 10, 50, and 100 Pa·s,presenting a p-value of 0.005, 0.006 and 0.03, respectively. Comparisonof Cement II to the Cement I group injected at 200 Pa·s resulted in atrend of reduced eccentricity for the Cement II (p=0.079), showngraphically in FIG. 12.

The Baroud Model was designed to favor leakage, representing a worstcase cement injection. In particular, the created leakage path of 3 mmis relatively large when compared to the demonstrated diameter fromvertebral veins of 0.5 to 2 mm. Furthermore, the relatively thick natureof the starch (bone marrow stimulant) makes it difficult to displace,thereby decreasing the uniformity of filling and increasing the risk ofcement leakage.

Clinical observations and investigations showed less to no leakage usingdifferent commercial vertebroplasty cements, for example, Cement I:Vertecem, Synthes GmbH; and Vertebroplastic, J&J DePuy Inc., at a startinjection viscosity of 50 Pa·s. Cement I injected at this viscositylevel demonstrated high leakage mass under the Baroud Model, thusconfirming that the Baroud Model used here favors leakage. Leaked massobserved for Cement I using starting injection viscosities below 400Pa·s were higher than that of Cement II, and comparable to Cement IIonly at viscosity levels around 400 Pa·s. The biggest difference inleaked mass investigated for Cement I could be observed between 100 Pa·sand 200 Pa·s. High scattering of the parameters could be due to themodel design using the 37° C. water bath.

Experimental results observed herein show a trend of reduced leakagerates and mass as starting viscosities increased for Cement I testing.These results correlate closely with the theoretical finding from theBaroud Model. Experimental results observed from Cement II showed lowleakage rates in the leakage favoring Baroud Model. The experimentalresults demonstrate Cement II can be utilized as a bone cement and readyfor injection substantially immediately after mixing and with little tono waiting phase. Cement II demonstrated a working time of at least 15min for the entire ambient temperature range from 19-27° C., and it isapplicable by using simple syringes allowing tactile feedback. ThusCement II has an initial injectable viscosity that reduces the waitingtime for commencing injection of the bone cement for example in avertebroplasty procedure. This initial injectability, in turn reducesthe risk of determining the proper injection time after mixing, e.g.,too early or too late injection, and therefore increased the safety ofthe intervention.

To estimate the injection viscosity necessary for Cement I todemonstrate a similar leakage mass as was obtained for Cement II underthe Baroud Model an extrapolation was performed A start injectionviscosity for Cement I of around 600 Pa·s yielded the same amount ofleaked mass as Cement II. In order to verify this phenomenologicalfinding concerning leakage, the consistency of the cements at differentviscosity levels was analyzed performing a visual inspection. Theinspection of the cement consistency was performed by extruding thecement out of a 1 ml syringe. Injection steps of 0.3 ml produced acement having a spaghetti-like appearance, as shown in FIGS. 14A-F. Thecement samples were extruded from the 1 ml syringe positionedhorizontally. Each injection step of 0.3 ml was about 2 sec. Cementconsistency was measured by observing the lengthening of the individualcement strands due to gravitational forces.

FIGS. 14A-F illustrates representative trials of the comparison of 0.3ml cement extruded out of the syringe for six groups investigated. Thevisual inspection of the consistency of Cement I at a viscosity of 600Pa·s, is shown in FIG. 14E in comparison to Cement II that was extrudedimmediately after preparation and having a measured viscosity of around80 Pa·s, shown in FIG. 14F. FIGS. 14E and 14F showed a close correlationin visual inspection.

Cement I extruded having a viscosity of around 10 Pa·s, necked andlengthened right after starting extrusion followed by disruption to thestrand (i.e., breaking) before the extrusion step could be finished. Ata starting viscosity of around 50 Pa·s, Cement I, shown in FIG. 14A, thedifference in behavior was visually in terms that the strand stayedstable longer and disrupted at the end of the injection phase.Observation while injecting Cement I having a viscosity of around 100Pa·s, shown in FIG. 14B revealed a stable strand for about 2 sec beforedisruption was noticed. At 200 Pa·s shown in FIG. 14C, Cement Iextrusion demonstrated a lengthening without disruption after severalseconds. Lengthening rate was reduced enormously using Cement I at aviscosity of 400 Pa·s and no disruption could be observed after severalseconds, as shown in FIG. 14D. As shown in FIG. 14E, Cement I having aviscosity of 600 Pa·s, and as shown in FIG. 14F Cement II as observedjust after preparation, reveals a very similar behavior. A stable cementspaghetti-like strand without any noticeable lengthening was noticed forboth samples after around 20 sec.

The investigation here showed that by increasing the waiting phase andthus the starting viscosity for injecting Cement I (Vertecem SynthesGmbH), the leakage mass decreased. However, Cement II showed very lowleakage mass in the Baroud Model favoring leakage when appliedsubstantially immediately after mixing. Cement II was ready to use oncethe solid and liquid component were mixed. As such, Cement II shortensthe waiting phase for a user, e.g., physician to substantially zerominutes without compromising the safety for the procedure.

Although the present disclosure has been described in accordance withseveral embodiments, it should be understood that various changes,substitutions, and alterations can be made herein without departing fromthe spirit and scope of the present disclosure, for instance asindicated by the appended claims. Thus, it should be appreciated thatthe scope of the present disclosure is not intended to be limited to theparticular embodiments of the process, manufacture, and composition ofmatter, methods and steps described herein. For instance, the variousfeatures as described above in accordance with one embodiment can beincorporated into the other embodiments unless indicated otherwise.Furthermore, as one of ordinary skill in the art will readily appreciatefrom the present disclosure, processes, manufacture, composition ofmatter, methods, or steps, presently existing or later to be developedthat perform substantially the same function or achieve substantiallythe same result as the corresponding embodiments described herein may beutilized according to the present disclosure.

It will be appreciated by those skilled in the art that variousmodifications and alterations of the invention can be made withoutdeparting from the broad scope of the appended claims. Some of thesehave been discussed above and others will be apparent to those skilledin the art.

What is claimed is:
 1. A bone cement formed by a combination of solidand liquid components comprising: a solid component including a contrastagent, a polymerization initiator, a calcium phosphate based bonesubstitute material, and a solid polymer, wherein the contrast agentincludes zirconium dioxide at about 40 percent by weight of the solidcomponent, the polymerization initiator in the range of about 0.3 toabout 0.5 percent by weight of the solid component, the bone substitutematerial includes hydroxyapatite at about 15 percent by weight of thesolid component, and the solid polymer includes a mixture ofpoly(methylacrylate-co-methylmethacrylate) and poly(methylmethacrylate)at about 45 percent by weight of the solid component, wherein thepoly(methylmethacrylate) is in the range of about 3 percent to about 15percent by weight percent of the solid polymer, and a liquid componentincluding a liquid monomer, a polymerization accelerator, andoptionally, a polymerization inhibitor; wherein the bone cement has aninitial injectable viscosity suitable for manual injection onto or intoa targeted anatomical location, and wherein said initial injectableviscosity being formed substantially immediately after combining thesolid component and liquid component.
 2. The bone cement according toclaim 1 wherein, the polymerization initiator is at about 0.4 percent ofthe solid component, and the liquid monomer includes methylmethacrylateat about 99.3 percent by weight of the liquid component, thepolymerization accelerator includes N—N-dimethyl-para-toluidine at about0.7 percent by weight of the liquid component, and optionally, thepolymerization inhibitor includes hydroquinone at about 60 ppm of theliquid component.
 3. The bone cement according to claim 1, wherein aftera hardening of the cement, the bone substitute material comprises about11 percent by weight of the hardened bone cement, the contrast agentcomprises about 29 percent by weight of the hardened bone cement, and,the solid polymer comprises about 60 percent by weight of the hardenedbone cement.
 4. The bone cement according to claim 1, wherein the solidpolymer has an average molecular weight range of about 200 kDa to about1000 kDa.
 5. The bone cement according to claim 4, wherein the solidpolymer has an average molecular weight range of about 600 kDa to about700 kDa.
 6. The bone cement according to claim 5, wherein the solidpolymer has an average molecular weight of substantially 600 kDa.
 7. Thebone cement according to claim 1, wherein the bone substitute materialcomprises sintered hydroxyapatite particles having an average particlediameter range of about 5 um to about 50 um.
 8. The bone cementaccording to claim 7, wherein the bone substitute material comprisessintered hydroxyapatite particles having an average particle diameterrange of about 10 um to about 30 um.
 9. The bone cement according toclaim 1, wherein the solid polymer comprises at least a portion ofsubstantially spherical polymerized beads.
 10. The bone cement accordingto claim 1, wherein the initial injectable viscosity is greater than 50Pa·s.
 11. The bone cement according to claim 1, wherein the bone cementhas a waiting time of about two minutes or less.
 12. The bone cementaccording to claim 1, wherein the bone cement has a waiting phase ofabout one minute or less.
 13. The bone cement according to claim 1,wherein the bone cement has a waiting time of about zero minutes. 14.The bone cement according to claim 1, wherein said targeted anatomicallocation is one or more vertebrae.
 15. The bone cement according toclaim 1, wherein, after application, the bone cement displays minimalleakage.
 16. A bone cement kit for treatment of a targeted anatomicallocation comprising: a first container housing a solid component, thesolid component comprising contrast agent, polymerization initiator,calcium phosphate based bone substitute material, and solid polymer,wherein the contrast agent includes zirconium dioxide at about 40percent by weight of the solid component, the polymerization initiatorin the range of about 0.3 to about 0.5 percent by weight of the solidcomponent, the bone substitute material includes hydroxyapatite at about15 percent by weight of the solid component, and the solid polymerincludes a mixture of poly(methylacrylate-co-methylmethacrylate) andpoly(methylmethacrylate) at about 45 percent by weight of the solidcomponent, wherein the poly(methylmethacrylate) is in the range of about3 percent to about 15 percent by weight percent of the solid polymer, asecond container containing a liquid component, the liquid componentcomprising liquid monomer, polymerization accelerator, and optionallypolymerization inhibitor; wherein the solid component and liquidcomponent are combinable to form a bone cement having an initialviscosity suitable for manual injection onto or into a targetedanatomical location with minimal leakage, and optionally one or moresyringes adapted to inject the bone cement.
 17. The bone cement kit ofclaim 16 wherein: the polymerization initiator includesdibenzoylperoxide at about 0.4 percent of the solid component, and, theliquid component includes about 99.4 percent by weightmethylmethacrylate, about 0.7 percent by weightN—N-dimethyl-para-toluidine, and about 60 ppm hydroquinone.
 18. The bonecement kit according to claim 17 wherein said targeted anatomicallocation is one or more vertebrae.
 19. A method for preparing the bonecement composition of claim 1, said method comprising the steps of:filling a first container with the solid component; filling a secondcontainer with the liquid component; and combining the liquid componentand the solid component using a mixer.
 20. A method for treating atargeted anatomical location with a bone cement comprising the step ofmanually injecting or applying the bone cement of claim 1 onto or intothe targeted anatomical location.
 21. The method of claim 20, whereinthe step of manually injecting includes manual actuation of a firstsyringe that produces a hydraulic pressure to effect the injection orapplication of the cement housed in a second syringe.
 22. The method ofclaim 20, wherein the targeting anatomical location is one or morevertebrae.
 23. A method for augmenting, replacing or treating, weakenedor collapsed vertebrae using bone cement, said method comprising thestep of manually injecting the bone cement of claim 1 onto or into oneor more vertebrae.
 24. The method of claim 23, wherein the step ofmanually injecting includes manual actuation of a first syringe thatproduces a hydraulic pressure to effect the injection or application ofthe cement housed in a second syringe.